Binding of Organic Cations to a Cyclophane Host As Studied with Molecular Dynamics Simulations and Free Energy Calculations

Abstract

We have studied the binding of two organic cations, an iminium (IM) and a guanidinium (GU), to a cyclophane host P4--4Na+, using molecular dynamics simulations and free energy calculations. A proper treatment of the long-range electrostatic forces is essential for the stability of these highly charged complexes, and a simple cutoff at 12 A results in an artifactual dissociation of the IM−P4--4Na+ complex. Since the host is highly aromatic and the guests cationic, cation−π interactions play an important role in the complex stability. In free energy calculations, using a simple additive force field, we calculate that the relative free energy of association of IM and GU binding to the host is 2.3 kcal/mol favoring IM, which is of the correct sign but 1.4 kcal/mol too small in magnitude. Differences in van der Waals interaction energies are mainly responsible for the different binding strengths, and the host adopts different shapes when accommodating IM compared to GU. To approximately estimate the contributi...